Previous work in the present project grant has contributed significantly to our understanding of the role of central nervous system corticotropin-releasing factor (CRF) and urocortin (Ucn) family neuropeptides and receptors in behavioral responses to stressors. In the previous funding period, the behavioral effects of CRF2 knockouts and urocortins were identified, leading to the hypothesis that brain CRF2 receptors have potential anti-stress and appetite-suppressing roles. Preliminary results in the previous funding period identified specific brain sites important for CRF-induced behavioral responses to stressors and Ucn-induced appetite suppression. The present proposal will test the hypothesis that CRF-related neuropeptides have a functional role in the central nervous system to mediate behavioral responses to stress. A subhypothesis is that CRF produces anxiogenic-like responses via CRF1 receptors in the central extended amygdala and that urocortins suppress appetite via CRF2 receptors in the hypothalamus. Specific Aim 1 will explore the role of the extended amygdala (medial and central nuclei of the amygdala, medial and lateral bed nucleus of the stria terminalis, and a transition zone in the medial nucleus accumbens) in the anti-stress-like effects of blockade of CRF1 receptors and of activation of CRF2 receptors. Specific Aim 2 will explore the role of specific nuclei in the hypothalamus in the suppression of feeding produced by CRF1 and CRF2 agonists using a microstructural meal pattern analysis approach in rats. Specific Aim 3 will explore the functional interaction of CRF1 and CRF2 receptor systems in the stress responses associated with activation or inactivation of CRF1 and CRF2 receptors in rats using pharmacological and lentiviral RNA interference approaches. Specific Aim 4 will use molecular murine models of constitutive Ucn deficiency or conditional transgenic CRF2 agonist overexpression to study the role of urocortins and CRF2 receptor activation in activation, stress and feeding behavioral responses. These studies will provide key information regarding the role of CRF-related neuropeptides and receptors in behavioral responses to stressors and regulation of appetite, and as a result may provide insights into the role of CRF system signaling in a variety of stress-related pathologies.